MECHANISMS OF RENAL TUBULAR EPITHELIAL CELL INJURY

描述：(改编自申请者的摘要)-这项计划的目标 建议阐明三磷酸腺苷的代谢和生化效应 造成主要功能后果的耗竭 肾小管上皮细胞亚致死性损伤。申请者将 关注亚致死性伤害的两个功能后果：丧失 细胞-基质黏附与活细胞从细胞上分离 基底膜和细胞-细胞间黏附丧失导致的损害 具有紧密连接功能。他们将研究亚致死的影响 对细胞细胞骨架的三个已知成分的损伤 在维持正常的紧密连接功能和 细胞-基质黏附；i)肌动蛋白细胞骨架；ii)黏附斑块； Iii)附着物交界处。这一应用程序的基础假设是： I)ATP耗尽的新陈代谢后果导致组织紊乱 肌动蛋白细胞骨架的变化，进而导致结构变化和 粘连连接和粘连斑块的功能损害，ii) 肌动蛋白细胞骨架的丢失是造成这些影响的原因 肌动蛋白结合蛋白酪氨酸磷酸化的失调 在粘连连接和粘连斑块内，以及iii) 防止酪氨酸磷酸化改变的干预措施 与ATP耗竭相关的将改善 亚致命性伤害。具体的目标是确定新陈代谢 导致细胞结构紊乱的ATP耗竭的后果 肌动蛋白细胞骨架，以检测ATP耗竭对酪氨酸的影响 构成粘附斑和粘附素的蛋白质的磷酸化 连接，并研究这些改变的磷酸化事件在 亚致死伤害的功能后果。

DESCRIPTION: (Adapted from the applicant's abstract) - The goals of this proposal are to elucidate the metabolic and biochemical effects of ATP depletion that are responsible for the major functional consequences of sublethal injury in renal tubular epithelial cells. The applicants will focus on two functional consequences of sublethal injury: loss of cell-matrix adhesion with resultant detachment of viable cells from the basement membrane and loss of cell-cell adhesion with consequent impairment of tight junction function. They will examine the effects of sublethal injury on three components of the cell cytoskeleton that are known to play an important role in maintaining normal tight junction function and cell-matrix adhesion; i) The actin cytoskeleton ii) the adhesion plaque, and iii) the adherens junction. The hypotheses underlying this application are: i) That the metabolic consequences of ATP depletion lead to disorganization of the actin cytoskeleton which in turn results in structural changes and function impairment of the adherens junctions and adhesion plaques, ii) that loss of the actin cytoskeleton is responsible for these effects by causing dysregulation of tyrosine phosphorylation of actin-binding proteins present within the adherens junctions and adhesion plaques, and iii) that interventions that prevent the changes in tyrosine phosphorylation associated with ATP depletion will ameliorate the functional consequences of sublethal injury. The specific aims are to identify the metabolic consequences of ATP depletion that result in structural disorganization of the actin cytoskeleton, to examine the effects of ATP depletion on tyrosine phosphorylation of proteins comprising the adhesion plaque and adherens junction, and to examine the role of these altered phosphorylation events in the functional consequences of sublethal injury.